Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: Differential effects by hippocampal size

Gustavo C. Román, Stephen Salloway, Sandra E. Black, Donald R. Royall, Charles DeCarli, Michael W. Weiner, Margaret Moline, Dinesh Kumar, Rachel Schindler, Holly Posner

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Background and Purpose: We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria. Methods: This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N≤974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. RESULTS: Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference,-1.156; 95% CI, -1.98 to-0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group. Conclusions: Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

Original languageEnglish (US)
Pages (from-to)1213-1221
Number of pages9
JournalStroke
Volume41
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Vascular Dementia
Randomized Controlled Trials
Placebos
Interviews
Vascular Diseases
Cognition
Caregivers
Atrophy
Alzheimer Disease
National Institute of Neurological Disorders and Stroke
donepezil
Neurosciences
Least-Squares Analysis
Observation
Outcome Assessment (Health Care)
Safety
Mortality
Incidence

Keywords

  • Donepezil
  • Efficacy
  • Hippocampal atrophy
  • Safety
  • Vascular dementia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia : Differential effects by hippocampal size. / Román, Gustavo C.; Salloway, Stephen; Black, Sandra E.; Royall, Donald R.; DeCarli, Charles; Weiner, Michael W.; Moline, Margaret; Kumar, Dinesh; Schindler, Rachel; Posner, Holly.

In: Stroke, Vol. 41, No. 6, 06.2010, p. 1213-1221.

Research output: Contribution to journalArticle

Román, GC, Salloway, S, Black, SE, Royall, DR, DeCarli, C, Weiner, MW, Moline, M, Kumar, D, Schindler, R & Posner, H 2010, 'Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: Differential effects by hippocampal size', Stroke, vol. 41, no. 6, pp. 1213-1221. https://doi.org/10.1161/STROKEAHA.109.570077
Román, Gustavo C. ; Salloway, Stephen ; Black, Sandra E. ; Royall, Donald R. ; DeCarli, Charles ; Weiner, Michael W. ; Moline, Margaret ; Kumar, Dinesh ; Schindler, Rachel ; Posner, Holly. / Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia : Differential effects by hippocampal size. In: Stroke. 2010 ; Vol. 41, No. 6. pp. 1213-1221.
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abstract = "Background and Purpose: We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria. Methods: This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N≤974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. RESULTS: Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference,-1.156; 95{\%} CI, -1.98 to-0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7{\%}), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group. Conclusions: Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.",
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AU - Black, Sandra E.

AU - Royall, Donald R.

AU - DeCarli, Charles

AU - Weiner, Michael W.

AU - Moline, Margaret

AU - Kumar, Dinesh

AU - Schindler, Rachel

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N2 - Background and Purpose: We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria. Methods: This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N≤974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. RESULTS: Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference,-1.156; 95% CI, -1.98 to-0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group. Conclusions: Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

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